A continuation of the studies of the biochemical mechanisms of action of psycho-active drugs is planned. The proposed studies will focus on the effects of antidepressant treatments on central serotonin (5HT) receptor mechanisms. Both radioligand binding analyses of presumed 5HT receptor sites and in vivo studies of 5HT behavioral sensitivity are planned. Chronic treatment with the antidepressants, amitriptyline and mianserin, decreases the density of 5HT2 binding sites (labelled with 3H-spiperone or 3H-ketanserin) in the frontal cortex of rats, with no significant changes in the 5HT1 binding site. It has been proposed that the subsensitivity of the 5HT2 site which follows treatment with these and other antidepressants may be related to their clinical efficacy. Studies are proposed to examine the mechanism of the decrease in the density of the 5HT2 binding site by mianserin, amitriptyline and desmethylimipramine. The studies will focus on explaining the differences in the onset of this response, in particular, the possible role of metabolic differences will be evaluated. Taking advantage of the marked changes in 5HT behavioral sensitivity and the 5HT2 binding site which are induced by chronic antidepressant treatments, the relationship between these events and the mechanism of these adaptive responses will be examined with the aim of understanding further if and how these changes relate to alterations in neuronal function. The role of noradrenergic neuronal input in the adaptive regulation of 5HT receptor systems and the possible relationship between the decrease in bets-adrenergic receptor sensitivity and the changes in 5HT sensitivity will be studied. The proposed studies will further test the hypothesis that alterations in 5HT-associated receptor systems may be related to the therapeutic action of antidepressants and also will lead to a clearer understanding of the function and regulation of central 5HT neuronal systems.